PROJECT SUMMARY/ABSTRACT Alzheimer's Disease (AD) is one of the most devastating neurological disorders, and is reaching epidemic proportions in the context of an aging U.S. population. Current treatment strategies have minimal impact and only slow the progression of the disorder once cognitive deficits are established. Thus, there is a clear need to identify persons at risk for AD pathology during the preclinical phase of the disorder, so that preventative strategies can be developed. Multiple emerging lines of research suggest excessive daytime sleepiness is a key precognitive symptom related to the Alzheimer's continuum. However, daytime somnolence is experienced by a large proportion of the general population, and is a non-specific symptom that can reflect myriad changes in brain function. To further advance this area of research, this project will clarify how specific objective measures of sleepiness are associated with AD biomarkers in the preclinical phase of the disorder. This study will address two Specific Aims and three related hypotheses targeted towards this vital area of inquiry. First, it will verify specific objective measures of sleepiness that map to increased ?-amyloid in brain regions susceptible to early deposition in preclinical AD. Specifically, it will build on preliminary findings that suggest infrared pupillometry, a measure of noradrenergic tone in the locus coeruleus, is reflective of increased ?-amyloid burden in the supramarginal gyrus. Additionally, it will test the hypothesis that a specific measure of daytime somnolence, the mean reaction time during the slowest 10% of responses on the psychomotor vigilance task, which has been previously connected to activity in the default mode network, will be associated with ?-amyloid deposition in the precuneus/posterior cingulate cortex, a key constituent of this network. Finally, this investigation will clarify whether phosphorylated and total tau protein in the cerebrospinal fluid are associated with findings from infrared pupillometry as hypothesized, given the locus coeruleus is the earliest site of abnormal tau deposition observed in AD. This research will be conducted in 75 well- characterized middle to older-aged adults participating in Wisconsin Alzheimer's Disease Research Center studies, and will leverage previously collected neuroimaging and biospecimen data, combined with prospective assessment of daytime sleepiness, longitudinal sleep-wake patterns, and sleep-related breathing disorders, to perform robust and well-controlled analyses. Addressing the Specific Aims of this application will have a sizeable impact on AD and sleep research, by linking measureable sleepiness phenotypes to associated pathological processes in the brain in preclinical AD. In so doing, this project will advance this vital area of inquiry in preclinical AD, that may lead to the development of improved screening and preventative therapeutic strategies for the disease.